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Pancreatic ductal adenocarcinoma (PDAC) represents a challenge in oncology, with limited treatment options for advanced-stage patients. Chimeric antigen receptor T cell (CAR T) therapy targeting mesothelin (MSLN) shows promise, but challenges such as the hostile immunosuppressive tumor microenvironment (TME) hinder its efficacy. This study explores the synergistic potential of combining proton radiation therapy (RT) with MSLN-targeting CAR T therapy in a syngeneic PDAC model. Proton RT significantly increased MSLN expression in tumor cells and caused a significant increase in CAR T cell infiltration into tumors. The combination therapy reshaped the immunosuppressive TME, promoting antitumorigenic M1 polarized macrophages and reducing myeloid-derived suppressor cells (MDSC). In a flank PDAC model, the combination therapy demonstrated superior attenuation of tumor growth and improved survival compared to individual treatments alone. In an orthotopic PDAC model treated with image-guided proton RT, tumor growth was significantly reduced in the combination group compared to the RT treatment alone. Further, the combination therapy induced an abscopal effect in a dual-flank tumor model, with increased serum interferon-γ levels and enhanced proliferation of extratumoral CAR T cells. In conclusion, combining proton RT with MSLN-targeting CAR T therapy proves effective in modulating the TME, enhancing CAR T cell trafficking, and exerting systemic antitumor effects. Thus, this combinatorial approach could present a promising strategy for improving outcomes in unresectable PDAC.
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Carcinoma Ductal Pancreático , Proteínas Ligadas por GPI , Imunoterapia Adotiva , Mesotelina , Neoplasias Pancreáticas , Receptores de Antígenos Quiméricos , Microambiente Tumoral , Animais , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/patologia , Camundongos , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia Adotiva/métodos , Microambiente Tumoral/imunologia , Humanos , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/radioterapia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Terapia com Prótons/métodos , Terapia Combinada , Linfócitos T/imunologia , FemininoRESUMO
BACKGROUND: Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that the metabolic stress induced by a KD combined with metformin would enhance radiation's efficacy. We sought to assess the tolerability and feasibility of this approach. METHODS: A single-institution phase I clinical trial. Radiotherapy was either 60 or 35 Gy over 6 or 2 weeks, for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a Modified Atkins Diet (ModAD) supplemented with medium chain triglycerides (MCT). There were three cohorts: Dietary intervention alone, and dietary intervention combined with low-dose or high-dose metformin; all patients received radiotherapy. Factors associated with blood ketone levels were investigated using a mixed-model analysis. RESULTS: A total of 13 patients were accrued, median age 61 years, of whom six had newly diagnosed and seven with recurrent disease. All completed radiation therapy; five patients stopped the metabolic intervention early. Metformin 850 mg three-times daily was poorly tolerated. There were no serious adverse events. Ketone levels were associated with dietary factors (ketogenic ratio, p < 0.001), use of metformin (p = 0. 02) and low insulin levels (p = 0.002). Median progression free survival was ten and four months for newly diagnosed and recurrent disease, respectively. CONCLUSIONS: The intervention was well tolerated. Higher serum ketone levels were associated with both dietary intake and metformin use. The recommended phase II dose is eight weeks of a ModAD combined with 850 mg metformin twice daily.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Glioma/tratamento farmacológico , Glioma/radioterapia , Humanos , Cetonas , Metformina/uso terapêutico , Pessoa de Meia-Idade , Recidiva Local de NeoplasiaRESUMO
BACKGROUND: In the current study we evaluated 68Ga PSMA PET/ CT to measure local control of bone metastasis in oligometastatic prostate cancer patients treated with SBRT. MATERIALS AND METHODS: After the institutional review board approval, a retrospective review of medical records of consecutive prostate cancer patients treated between 2014 and 2018 was conducted. Only medical records of patients that were treated with SBRT for bone metastasis and had pre-and post-SBRT 68Ga PSMA PET/CT scans were included in our study. Data extracted from the medical files included patient-related (age), disease-related (Gleason score, site of metastasis), and treatment-related factors and outcomes. RESULTS: During the study period, a total of 12 patients (15 lesions) were included, with a median age of 73 years. The median follow-up was 26.5 months (range 13-45 months). Median time of 68Ga PSMA PET/ CT follow up was 17.0 months (range 3-39 months). The median pre-treatment PSA was 2 ng/mL (range 0.56-44 ng/mL) vs. post treatment PSA nadir of 0.01 ng/mL (0.01-4.32) with a median time to nadir of 7 months (range, 2-12). Local control was 93% during the follow up period and there was correlation with PS MA avidity on PE T. None patients developed recurrences in the treated bone. None of the patients had grade 3 or more toxicities during follow-up. CONCLUSIONS: SBRT is a highly effective and safe method for treatment of prostate cancer bone metastases. More studies are required to determine if SBRT provides greater clinical benefit than standard fractionation for oligometastatic prostate cancer patients. 68Ga PSMA PET/CT should be further investigated for delineation and follow-up.
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One of the most ambitious goals in modern cardiology is to regenerate the injured myocardium. The human myocardium has poor regenerative power. Thus, significant myocardial injury results in irreversible damage, scar formation, remodeling, and dysfunction. The search for therapies that will improve myocardial regeneration needs a better understanding of the mechanisms of repair and regeneration. While the role of macrophages in inflammation, scar formation, and fibrosis are well defined, their role in myocardial regeneration is less clear. Recent reports have suggested that cardiac macrophages regulate myocardial regeneration in neonatal mice. The present review aims to describe the latest discoveries about the possible role of macrophages in myocardial regeneration. We discuss the promises and difficulties to translate the latest findings into new therapies.
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Coração/fisiologia , Macrófagos/fisiologia , Regeneração/fisiologia , Animais , Humanos , Inflamação/patologia , Modelos BiológicosRESUMO
BACKGROUND: Little is known about the potentially unfavorable effects of mesenchymal stromal cell (MSC) activation on the heart. MSCs can respond to tissue injury by anti- or proinflammatory activation. We aimed to study the potential negative interaction between left ventricular dysfunction (LVD) and MSC activation. METHODS: We isolated MSCs from cardiac and subcutaneous fat tissues of mice with LVD 28 days after myocardial infarction or sham operation. To evaluate the effect of LVD on MSCs, we characterized cardiac MSCs and subcutaneous MSCs in vitro. Subsequently, we injected MSCs or saline into the infarcted myocardium of mice and evaluated LV remodeling and function 28 days after myocardial infarction. To test the hypothesis that toll-like receptor 4 (TLR4) mediates proinflammatory polarization of MSCs, we characterized cardiac MSCs from TLR4-/- and wild-type (WT) mice after inflammatory stimulation in vitro. Next, we transplanted cardiac MSCs from TLR4-/- and WT male mice into the infarcted myocardium of female WT mice and evaluated infarct size, MSC retention, inflammation, remodeling, and function after 7 days. RESULTS: LVD switched cardiac MSCs toward an inflammatory phenotype, with increased secretion of inflammatory cytokines as well as chemokines. The effect of LVD on subcutaneous MSCs was less remarkable. Although transplantation of cardiac MSCs and subcutaneous MSCs from LVD and sham hearts did not improve LV remodeling and function, cardiac MSCs from LVD exacerbated anterior wall thinning 28 days after myocardial infarction. The inflammatory polarization of cardiac MSCs by LVD was mediated by TLR4, as we found less secretion of inflammatory cytokines and higher secretion of anti-inflammatory cytokines from activated cardiac MSCs of TLR4-deficient mice, compared with WT cardiac MSCs. Significantly, TLR4 deficiency preserved the expression of CD47 (don't eat me signal) on cardiac MSCs after both TLR4 stimulation in vitro and transplantation into the infarcted heart. Compared with WT cardiac MSCs and saline, TLR4-/- cardiac MSCs survived in the cardiac tissue and maintained their reparative properties, reduced infarct size, increased scar thickness, and attenuated LV dilatation 7 days after myocardial infarction. CONCLUSIONS: The environment of the failing and infarcted myocardium drives resident and transplanted MSCs toward a proinflammatory phenotype and restricts their survival and reparative effects in a mechanism mediated by TLR4.
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Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Fenótipo , Receptor 4 Toll-Like/deficiência , Disfunção Ventricular Esquerda/patologia , Animais , Células Cultivadas , Feminino , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos TransgênicosRESUMO
Kingella kingae is an encapsulated gram-negative organism that is a common cause of osteoarticular infections in young children. In earlier work, we identified a glycosyltransferase gene called csaA that is necessary for synthesis of the [3)-ß-GalpNAc-(1â5)-ß-Kdop-(2â] polysaccharide capsule (type a) in K. kingae strain 269-492. In the current study, we analyzed a large collection of invasive and carrier isolates from Israel and found that csaA was present in only 47% of the isolates. Further examination of this collection using primers based on the sequence that flanks csaA revealed three additional gene clusters (designated the csb, csc, and csd loci), all encoding predicted glycosyltransferases. The csb locus contains the csbA, csbB, and csbC genes and is associated with a capsule that is a polymer of [6)-α-GlcpNAc-(1â5)-ß-(8-OAc)Kdop-(2â] (type b). The csc locus contains the cscA, cscB, and cscC genes and is associated with a capsule that is a polymer of [3)-ß-Ribf-(1â2)-ß-Ribf-(1â2)-ß-Ribf-(1â4)-ß-Kdop-(2â] (type c). The csd locus contains the csdA, csdB, and csdC genes and is associated with a capsule that is a polymer of [P-(Oâ3)[ß-Galp-(1â4)]-ß-GlcpNAc-(1â3)-α-GlcpNAc-1-] (type d). Introduction of the csa, csb, csc, and csd loci into strain KK01Δcsa, a strain 269-492 derivative that lacks the native csaA gene, was sufficient to produce the type a capsule, type b capsule, type c capsule, and type d capsule, respectively, indicating that these loci are solely responsible for determining capsule type in K. kingae. Further analysis demonstrated that 96% of the invasive isolates express either the type a or type b capsule and that a disproportionate percentage of carrier isolates express the type c or type d capsule. These results establish that there are at least four structurally distinct K. kingae capsule types and suggest that capsule type plays an important role in promoting K. kingae invasive disease.
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Cápsulas Bacterianas/química , Proteínas de Bactérias/química , Kingella kingae/patogenicidade , Infecções por Neisseriaceae/patologia , Polissacarídeos Bacterianos/química , Cromatografia em Gel , Cromatografia Gasosa-Espectrometria de Massas , Genes Bacterianos , Glicosiltransferases/genética , Kingella kingae/genética , Virulência/fisiologiaRESUMO
Background: During the past 2 decades, numerous clinical trials have focused on improving outcomes in patients with metastatic pancreatic cancer (mPDAC). The efficacy of new treatments has been demonstrated among highly selected patients in randomized phase III trials; hence, it is not clear to what extent these advances are reflected within the broader mPDAC population. Materials and Methods: Survival statistics were extracted from the SEER database for patients diagnosed with mPDAC between 1993 and 2013. Survival was analyzed using the Kaplan-Meier method and proportional hazard models. Results: The study population consisted of 57,263 patients diagnosed with mPDAC between 1993 and 2013; 52% were male, with a median age of 69 years (range, 15-104). Superior prognosis correlated with younger age, being married, tumor located within the head of the pancreas, lower grade disease, and more recent year of diagnosis. Median overall survival (OS) remained stable at 2 months between 1993 and 2013. Improvements in OS were seen for younger patients (age <50 years) and those with a more recent year of diagnosis (2009-2013). The percentage of patients who died within 2 months of initial diagnosis decreased between 1993 and 2013 (from 63.5% to 50.6%; P<.0001). The percentage of patients surviving ≥12 months improved from 4.9% in 1993 to 12.7% in 2013 (P<.0001). Conclusions: In recent years a modest improvement in OS has been seen among younger patients with mPDAC. The percentage of patients living beyond 1 year has significantly increased over time; however, the percentage of those dying within 2 months remains substantial.
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Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Sobreviventes de Câncer , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Adenocarcinoma/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Neoplasias Pancreáticas/epidemiologia , Vigilância da População , Modelos de Riscos Proporcionais , Sistema de Registros , Programa de SEER , Estados Unidos/epidemiologia , Neoplasias PancreáticasRESUMO
High-throughput omics have proven invaluable in studying human disease, and yet day-to-day clinical practice still relies on physiological, non-omic markers. The metabolic syndrome, for example, is diagnosed and monitored by blood and urine indices such as blood cholesterol levels. Nevertheless, the association between the molecular and the physiological manifestations of the disease, especially in response to treatment, has not been investigated in a systematic manner. To this end, we studied a mouse model of diet-induced dyslipidemia and atherosclerosis that was subject to various drug treatments relevant to the disease in question. Both physiological data and gene expression data (from the liver and white adipose) were analyzed and compared. We find that treatments that restore gene expression patterns to their norm are associated with the successful restoration of physiological markers to their baselines. This holds in a tissue-specific mannertreatments that reverse the transcriptomic signatures of the disease in a particular tissue are associated with positive physiological effects in that tissue. Further, treatments that introduce large non-restorative gene expression alterations are associated with unfavorable physiological outcomes. These results provide a sound basis to in silico methods that rely on omic metrics for drug repurposing and drug discovery by searching for compounds that reverse a disease's omic signatures. Moreover, they highlight the need to develop drugs that restore the global cellular state to its healthy norm rather than rectify particular disease phenotypes.
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Anti-Inflamatórios/farmacologia , Biomarcadores/análise , Dislipidemias/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Transcriptoma/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Dislipidemias/genética , Humanos , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Especificidade de ÓrgãosAssuntos
Cardiomiopatias/patologia , Miócitos Cardíacos/metabolismo , Cardiomiopatias/metabolismo , Estudos de Casos e Controles , Diferenciação Celular , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/citologia , Período Periparto , Fator de Transcrição STAT3/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Cardiovascular disease (CVD) and cancer are among the leading causes of morbidity and mortality globally, and these conditions are increasingly recognized to be fundamentally interconnected. In this Review, we present the current epidemiological data for each of the modifiable risk factors shared by the two diseases, including hypertension, hyperlipidaemia, diabetes mellitus, obesity, smoking, diet, physical activity and the social determinants of health. We then review the epidemiological data demonstrating the increased risk of CVD in patients with cancer, as well as the increased risk of cancer in patients with CVD. We also discuss the shared mechanisms implicated in the development of these conditions, highlighting their inherent bidirectional relationship. We conclude with a perspective on future research directions for the field of cardio-oncology to advance the care of patients with CVD and cancer.
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Doenças Cardiovasculares , Neoplasias , Humanos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Neoplasias/epidemiologia , Fatores de Risco , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/fisiopatologia , Medição de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Hipertensão/complicações , Diabetes Mellitus/epidemiologiaRESUMO
BACKGROUND: Biliary tract cancers (BTC) are rare and aggressive malignancies originating from intrahepatic and extrahepatic bile ducts and the gallbladder. Surgery is the only curative option, but due to late-stage diagnosis, is frequently not feasible, leaving chemotherapy as the primary treatment. Radiotherapy (RT) can be an effective alternative for patients with unresectable, non-metastatic BTC despite the generally poor prognosis and significant variability. To help manage patients with unresectable BTC who receive RT, we aimed to identify prognostic markers that could aid in predicting overall survival (OS). METHODS: A retrospective cohort study was conducted at the University of Pennsylvania, involving seventy-eight patients with unresectable BTC treated with definitive intent RT. Comprehensive demographic, clinical, and treatment-related data were extracted from the electronic medical records. Univariate and multivariate Cox regressions were employed to identify predictors of OS after RT. A biomarker model was developed for refined survival prediction. RESULTS: The cohort primarily comprised patients with good performance status without significant hepatic dysfunction at presentation. The predominant treatment approach involved hypofractionated RT or concurrent 5FU-based chemoRT. Median OS after RT was 12.3 months, and 20 patients (15.6%) experienced local progression with a median time of 30.1 months. Univariate and multivariate analyses identified CA19-9 (above median) and higher albumin-bilirubin (ALBI) grades at presentation as significant predictors of poor OS. Median OS after RT was 24 months for patients with no risk factors and 6.3 months for those with both. CONCLUSIONS: Our study demonstrates generally poor but significantly heterogeneous OS in patients with unresectable BTC treated with RT. We have developed a biomarker model based on CA19-9 and ALBI grade at presentation that can distinguish sub-populations with markedly diverse prognoses. This model can aid the clinical management of this challenging disease.
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Neoplasias do Sistema Biliar , Humanos , Feminino , Masculino , Estudos Retrospectivos , Neoplasias do Sistema Biliar/radioterapia , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Pessoa de Meia-Idade , Idoso , Prognóstico , Adulto , Idoso de 80 Anos ou mais , Taxa de Sobrevida , Medição de RiscoRESUMO
BACKGROUND: Lymphopenia and high neutrophil-to-lymphocyte ratio are known negative prognostic factors in rectal cancer. Until recently, however, lymphopenia was regarded as a minor sequela following radiation therapy (RT). The immune system's influence on rectal cancer treatment outcomes led us to evaluate the impact of lymphopenia at various time points, before, during, and following radiotherapy. We hypothesized that chronic lymphopenia following radiotherapy might negatively influence the survival of patients, and pre-treatment lymphopenia may be predictive of poor outcomes. METHODS: This retrospective study involved 110 patients treated for rectal cancer between 2015 and 2019. The oncological outcomes are defined as alive without disease (AWOD), alive with disease (AWD), and death. These outcome probabilities tested against variables of lymphopenia before RT, during RT, and at several post-RT follow-up time points. RESULTS: At the end of the study, 69 patients were AWOD (63 %), 13 were AWD (12 %) and 28 had died (25 %). Treatment results were assessed with according level of lymphocytes measured one year following RT: 35 out of 39 patients (89.7 %) with normal values were AWOD. In 65 patients with sustained lymphopenia, 52 % were AWOD, 18.5 % AWD and 29 % died. A similar difference was found at all time-points up to 2 years following RT (p < 0.004). The results of our study shows that pre-existing lymphopenia (prior to RT) is associated with a 3 times greater chance of death compared to patients with normal lymphocyte levels prior to RT. The PFS significantly affected by lymphopenia at all time-points after RT. An NLR of more than 4 was associated with a 3-time higher risk of recurrence than lower NLR scores (p = 0.0054). CONCLUSION: Our results support the relevance of lymphopenia and NLR in the prognosis of rectal cancer. We believe this is the first study showing a negative correlation between sustained lymphopenia and OS following RT.
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ABSTRACT: It is increasingly recognized that heterogeneities in tumor response and severity of adverse effects in irradiated patients can be attributed to the tumor microenvironment and host-related factors. Among the latter, a growing body of literature in recent years has demonstrated the role of the patient's microbiome in modulating both tumor and normal tissue response to radiotherapy (RT). Upon contact with the environment after birth, the infant's gastrointestinal tract is rapidly colonized by microbiota, which is low in diversity and predominantly characterized by 2 dominant species, Actinobacteria and Proteobacteria. With time, intestinal microbiota diversity increases, and colonization of Firmicutes and Bacteroidetes becomes dominant. By the time a child reaches 3 years, the gut microbiota composition has been reshaped and is relatively similar to that of an adult. The microbiome colonizing the different body organs comprises various species and abundances, which may impact human health. Although the adult microbiome composition is thought to remain stable in health, microbiome diversity and composition respond to different environmental and pathological conditions, including pharmaceutical interventions and RT. Our review focuses on how the gut microbiota modulates normal tissue toxicity and tumor control. Readers who want to learn more about how RT shapes gut microbiome diversity and composition are referred to several excellent recently published reviews.
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Microbioma Gastrointestinal , Microbiota , Adulto , Lactente , Criança , Humanos , Firmicutes , Proteobactérias , BacteroidetesRESUMO
BACKGROUND: Fatigue is thought of as a leading cause of iatrogenic accidents. A significant deterioration in qualitative balance function has been shown in sleep deprived individuals. AIM/OBJECTIVES: To quantify the degree to which balance is impaired by sleep deprivation (SD) in post-call medical residents. METHODS: Medical residents voluntarily underwent computed dynamic posturography (CDP) before and after an on-call night, at an identical time of the day. Order of test performance was random to avoid behavioral learning. Each participant served as his or her own control. RESULTS: Seventeen residents were enrolled (median age 32years). Average sleeping duration the night before and during the night shift was 6.5 and 1 hour, respectively. The average response times difference between alert and fatigued was 10.15 milliseconds (95% CI: 6.81-13.49 milliseconds), yielding a significantly prolonged response times from 120 milliseconds before to 130 milliseconds after the night shift (P < .001). Comparison of additional measurements of CDP performance did not differ between test conditions. CONCLUSION: Medical residents are fatigued due to the effect of on-call nights. Sleep deprivation prolongs response times to vestibular stimuli. This finding probably has an effect on execution of manual skills and may reflect a more generalized slowing of responses and overall performance impairment. SIGNIFICANCE: The vestibular system is susceptible to SD.
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Internato e Residência , Privação do Sono , Humanos , Masculino , Feminino , Adulto , Sono , Duração do Sono , Tolerância ao Trabalho Programado , Fadiga/etiologiaRESUMO
INTRODUCTION: Chemokine (C-X3-C Motif) Receptor 1 (CX3CR1) is present in a subset of the immune cells in the tumor microenvironment (TME) and plays an essential and diverse role in cancer progression. However, its potential function in the irradiated TME remains unknown. MATERIALS AND METHODS: A mouse lung cancer model was performed by subcutaneously inoculating Lewis Lung Carcinoma (LLC) cells expressing luciferase (Luc-2) and mCherry cells in CX3CR1GFP/GFP, CX3CR1DTR/+, and wild-type (WT) mice. Bioluminescence imaging, clonogenic assay, and flow cytometry were used to assess tumor progression, proliferation, and cell composition after radiation. RESULTS: Radiation provoked a significant influx of CX3CR1-expressing immune cells, notably monocytes and macrophages, into the TME. Co-culturing irradiated LLC cells with CX3CR1-deficient monocytes, and macrophages resulted in reduced clonogenic survival and increased apoptosis of the cancer cells. Interestingly, deficiency of CX3CR1 in macrophages led to a redistribution of the irradiated LLC cells in the S-phase, parallel to increased expression of cyclin E1, required for cell cycle G1/S transition. In addition, the deficiency of CX3CR1 expression in macrophages altered the cytokine secretion with a decrease in interleukin 6, a crucial mediator of cancer cell survival and proliferation. Next, LLC cells were injected subcutaneously into CX3CR1DTR/+ mice, sensitive to diphtheria toxin (DT), and WT mice. After injection, tumors were irradiated with 8 Gy, and mice were treated with DT, leading to conditional ablation of CX3CR1-expressing cells. After three weeks, CX3CR1-depleted mice displayed reduced tumor progression. Furthermore, combining the S-phase-specific chemotherapeutic gemcitabine with CX3CR1 cell ablation resulted in additional attenuation of tumor progression. CONCLUSIONS: CX3CR1-expressing mononuclear cells invade the TME after radiation therapy in a mouse lung cancer model. CX3CR1 cell depletion attenuates tumor progression following radiation and sensitizes the tumor to S-phase-specific chemotherapy. Thus, we propose a novel strategy to improve radiation sensitivity by targeting the CX3CR1-expressing immune cells.
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Aim To compare the 1-year survival rate of patients with atrial fibrillation (AF) following left atrial appendage occluder (LAAO) implantation vs. treatment with novel oral anticoagulants (NOACs). METHODS: We have conducted an indirect, retrospective comparison between LAAO and NOAC registries. The LAAO registry is a national prospective cohort of 419 AF patients who underwent percutaneous LAAO between January 2008 and October 2015. The NOACs registry is a multicenter prospective cohort of 3138 AF patients treated with NOACs between November 2015 and August 2018. Baseline patient characteristics were retrospectively collected from coded diagnoses of hospitalization and outpatient clinic notes. Follow-up data was sorted from coded diagnoses and the national civil registry. Subjects were matched according to propensity score. Baseline characteristics were compared using Chi-Square and student's t-test. Survival analysis was performed using Kaplan-Meier survival curves, log-rank test, and multivariable Cox regression, adjusting for possible confounding variables. RESULTS: This study included 114 subjects who underwent LAAO implantation and 342 subjects treated with NOACs. The mean age of participants was 77.9 ± 7.44 and 77.1 ± 11.2 years in the LAAO and NOAC groups, respectively (p = 0.4). The LAAO group had 70 (61%) men compared to 202 (59%) men in the NOAC group (p = 0.74). No significant differences were found in baseline comorbidities, renal function, or CHA2DS2-VASc score. One-year mortality was observed in 5 (4%) patients and 32 (9%) patients of the LAAO and NOAC groups, respectively. After adjusting for confounders, LAAO was significantly associated with a lower risk for 1-year mortality (HR 0.38, 95%CI 0.14-0.99). In patients with impaired renal function, this difference was even more prominent (HR 0.21 for creatinine clearance (CrCl) < 60 mL/min). CONCLUSIONS: In a pooled analysis of two registries, we found a significantly lower risk for 1-year mortality in patients with AF who were implanted with LAAO than those treated with NOACs. This finding was more prominent in patients with impaired renal function. Future prospective direct studies should further investigate the efficacy and adverse effects of both treatment strategies.
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BACKGROUND: With advances in understanding liver tolerance, conformal techniques, image guidance, and motion management, dose-escalated radiotherapy has become a potential treatment for inoperable hepatocellular carcinoma (HCC). We aimed to evaluate the possible impact of biologically effective dose (BED) on local control and toxicity among patients with HCC. METHODS AND MATERIALS: Patients treated at our institution from 2009 to 2018 were included in this retrospective analysis if they received definitive-intent radiotherapy with a nominal BED of at least 60 Gy. Patients were stratified into small and large tumors using a cutoff of 5 cm, based on our clinical practice. Toxicity was assessed using ALBI scores and rates of clinical liver function deterioration. RESULTS: One hundred and twenty-eight patients were included, with a mean follow-up of 16 months. The majority of patients (90.5%) had a good performance status (ECOG 0-1), with Child-Pugh A (66.4%) and ALBI Grade 2 liver function at baseline (55.4%). Twenty (15.6%) patients had a local recurrence in the irradiated field during the follow-up period. Univariate and multivariate Cox proportional hazard analyses showed that only BED significantly predicted local tumor recurrence. Higher BED was associated with improved local control in tumors with equivalent diameters over 5 cm but not in smaller tumors. There was no difference in liver toxicity between the low and high-dose groups. CONCLUSIONS: Higher radiotherapy dose is associated with improved local control in large tumors but not in tumors smaller than 5 cm in diameter. High-dose radiotherapy was not associated with increased liver toxicity.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/patologia , Estudos Retrospectivos , Doses de RadiaçãoRESUMO
BACKGROUND: Despite the increasing recognition of Kingella kingae as an important pathogen of early childhood, the relative frequency and invasiveness of different strains of the organism has not been investigated. A study was conducted to determine the association of K. kingae genotypes with specific clinical syndromes and the temporal and geographic distribution of invasive clones. METHODS: A collection of 181 invasive K. kingae strains, isolated between 1991 and 2012 from Israeli patients with bacteremia, skeletal system infections, or endocarditis, were typed by pulsed-field gel electrophoresis (PFGE). In addition, the correspondence between PFGE, multilocus sequence types (MLSTs), and rtxA gene sequencing results was also examined for organisms belonging to the predominant PFGE clones isolated from asymptomatic carriers and patients with invasive infections. RESULTS: A total of 32 different K. kingae clones were identified by PFGE, of which 5 (B, H, K, N, and P) caused 72.9% of all invasive infections, and were recovered during the 21-year period from different regions of the country. Clone K was significantly associated with bacteremia, clone N with skeletal system infections, and clone P with bacterial endocarditis. Strains belonging to the same PFGE clone, either carried asymptomatically or causing different invasive infections, shared MLST complexes and exhibited identical or closely related rtxA alleles. CONCLUSIONS: Although K. kingae exhibits noteworthy genetic heterogeneity, a limited number of distinct clones cause the majority of invasive infections in Israel, exhibiting genetic stability, long-term persistence, and wide geographic dispersal. K. kingae strains also show significant association with specific clinical syndromes.
Assuntos
Kingella kingae/genética , Infecções por Neisseriaceae/microbiologia , Adulto , Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Doenças Ósseas Infecciosas/epidemiologia , Doenças Ósseas Infecciosas/microbiologia , Distribuição de Qui-Quadrado , Criança , Eletroforese em Gel de Campo Pulsado , Endocardite Bacteriana/epidemiologia , Endocardite Bacteriana/microbiologia , Técnicas de Genotipagem/métodos , Humanos , Israel/epidemiologia , Kingella kingae/classificação , Infecções por Neisseriaceae/epidemiologiaRESUMO
To evaluate effects of Continuous Positive Airway Pressure (CPAP) on cardiac position, volume, and motion in a cohort of patients receiving thoracic radiation therapy (RT). Patients underwent 3-dimensional (3D) and 4D-computerized tomography (CT) imaging with free-breathing (FB) and CPAP for RT planning. All scans were co-registered on the treatment planning system for contouring, identification of the center of heart volume and comparative measurements of cardiac displacement, volume and motion. Heart volume (HV) was created from 3D-CT contours. Range of heart motion was estimated by creating an internal heart volume (IHV) from 4D-CT contours. Magnitude of cardiac motion (cardiac excursion) was recorded as the difference in volume between IHV and HV. Wilcoxon signed rank test and Spearmen's rank correlation coefficient were used to assess differences between variables and correlations between lung volume and heart parameters. Results from 9 patient data sets were available for this report. Compared to FB, CPAP use was associated with caudal displacement of the HV (1 cm, p < 0.008) and IHV (1.1 cm, p < 0.008). CPAP use decreased HV 6% (p < 0.008) and IHV 13% (p < 0.008). Cardiac excursion was 49% (p < 0.01) less with CPAP than with FB. CPAP use increased mean lung volume by 30% (p < 0.008) which correlated with caudal displacement of the HV (râ¯=â¯0.83, p < 0.008) and IHV (râ¯=â¯0.98, p < 0.001). The use of CPAP reduced cardiac motion and volume although the reduction in volume was minimal. The increase in lung volume correlated with caudal displacement of the heart. These results suggest the mechanism for achieving dosimetric benefit was obtained by cardiac displacement and decreased lung and heart motion rather than reduction of HV. Further evaluation of CPAP as a novel technique to reduce heart exposure when offering RT is warranted.